Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Cell Transplant. 2010;19(4):369-86. doi: 10.3727/096368909X484266. Epub 2009 Dec 18.
In this study, we have investigated the hypothesis that previously reported beneficial effect of peripheral blood mononuclear cells cultured under angiogenic conditions on cardiovascular function following ischemia is not limited to EPCs but also to monocytes contained therein. We first purified and analyzed the phenotype and secretome of human and murine blood monocytes cultured under angiogenic conditions (named MDs for monocyte derivatives) and tested their effect in a mouse model of myocardial infarction (MI). FACS analysis of MDs shows that these cells express mature endothelial cell markers and that their proliferative capacity is virtually absent, consistent with their end-differentiated monocytic ontogeny. MDs secreted significant levels of HGF, IGF-1, MCP-1, and sTNFR-1 relative to their monocyte precursors. MDs were unable to form vascular networks in vitro when cultured on matrix coated flasks. Treatment of murine HL-1 cardiomyocyte cell line with MD-conditioned medium reduced their death induced by TNF-alpha, staurosporine, and oxidative stress, and this effect was dependent upon MD-derived sTNFR-1, HGF, and IGF-1. We further demonstrate that MD secretome promoted endothelial cell proliferation and capacity to form vessels in vitro and this was dependent upon MD-derived MCP-1, HGF, and IGF-1. Echocardiography analysis showed that MD myocardial implantation improved left ventricle fractional shortening of mouse hearts following MI and was associated with reduced myocardial fibrosis and enhancement of angiogenesis. Transplanted MDs and their secretome participate in preserving functional myocardium after ischemic insult and attenuate pathological remodeling.
在这项研究中，我们研究了一个假设，即在缺血后，先前报道的在血管生成条件下培养的外周血单核细胞对心血管功能的有益作用不仅限于 EPC，还包括其中所含的单核细胞。我们首先纯化并分析了在血管生成条件下培养的人源和鼠源血液单核细胞（命名为单核细胞衍生细胞，简称 MDs）的表型和分泌组，并在心肌梗死（MI）的小鼠模型中测试了它们的作用。MDs 的 FACS 分析表明，这些细胞表达成熟的内皮细胞标志物，并且其增殖能力几乎不存在，与它们终末分化的单核细胞发生相一致。MDs 分泌的 HGF、IGF-1、MCP-1 和 sTNFR-1 的水平与单核细胞前体相比显著升高。当在涂有基质的培养瓶中培养时，MDs 无法在体外形成血管网络。用 MD 条件培养基处理 HL-1 心肌细胞系可减少 TNF-α、星形孢菌素和氧化应激诱导的细胞死亡，这种作用依赖于 MD 衍生的 sTNFR-1、HGF 和 IGF-1。我们进一步证明，MD 分泌组促进了内皮细胞的增殖和体外形成血管的能力，这依赖于 MD 衍生的 MCP-1、HGF 和 IGF-1。超声心动图分析表明，MD 心肌植入可改善 MI 后小鼠心脏的左心室短轴缩短率，并伴有心肌纤维化减少和血管生成增强。移植的 MDs 及其分泌组参与了缺血损伤后保存功能心肌的过程，并减轻了病理性重塑。
